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Found 35755 matches. Displaying 111-120
Weisel K, Berger S, Papp K, Maari C, Krueger JG, Scott N, Tompson D, Wang S, Simeoni M, Bertin J, Tak PP
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Response to Inhibition of Receptor-Interacting Protein Kinase 1 (RIPK1) in Active Plaque Psoriasis: A Randomized Placebo-Controlled Study

CLINICAL PHARMACOLOGY & THERAPEUTICS 2020 OCT; 108(4):808-816
Receptor-interacting protein kinase 1 (RIPK1), a regulator of inflammation and cell death, is a potential therapeutic target in immune-mediated inflammatory diseases (IMIDs). The objective of this phase IIa multicenter, randomized, double-blind, placebo-controlled study was to evaluate safety, tolerability pharmacokinetics, pharmacodynamics, and preliminary efficacy of GSK2982772, a RIPK1 inhibitor, in plaque-type psoriasis. Psoriasis patients (N = 65) were randomized to 60 mg twice daily (b.i.d.) or three times daily (t.i.d.), or placebo for 84 days. Most adverse events (AEs) were mild with no severe drug-related AEs reported. Plaque Lesion Severity Sum improved with b.i.d. treatment compared with placebo; interpretation of t.i.d. treatment results was complicated by a high placebo response. Reductions in epidermal thickness and infiltration by CD3+ T cells in the epidermis and dermis were observed compared with placebo. Results support the rationale for additional studies on RIPK1 inhibition in IMIDs.
Su MF, Zhu L, Zhang YX, Paknejad N, Dey R, Huang JY, Lee MY, Williams D, Jordan KD, Eng ET, Ernst OP, Meyerson JR, Hite RK, Walz T, Liu W, Huang XY
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Structural Basis of the Activation of Heterotrimeric Gs-Protein by Isoproterenol-Bound beta(1)-Adrenergic Receptor

MOLECULAR CELL 2020 OCT 1; 80(1):59-71.e4
Cardiac disease remains the leading cause of morbidity and mortality worldwide. The beta(1)-adrenergic receptor (beta(1)-AR) is a major regulator of cardiac functions and is downregulated in the majority of heart failure cases. A key physiological process is the activation of heterotrimeric G-protein Gs by beta(1)-ARs, leading to increased heart rate and contractility. Here, we use cryo-electron microscopy and functional studies to investigate the molecular mechanism by which beta(1)-AR activates Gs. We find that the tilting of alpha 5-helix breaks a hydrogen bond between the sidechain of His373 in the C-terminal alpha 5-helix and the backbone carbonyl of Arg38 in the N-terminal alpha N-helix of Ga-s. Together with the disruption of another interacting network involving Gln59 in the alpha 1-helix, Ala352 in the beta 6-alpha 5 loop, and Thr355 in the alpha 5-helix, these conformational changes might lead to the deformation of the GDP-binding pocket. Our data provide molecular insights into the activation of G-proteins by G-protein-coupled receptors.
Sandifer P, Knapp L, Lichtveld M, Manley R, Abramson D, Caffey R, Cochran D, Collier T, Ebi K, Engel L, Farrington J, Finucane M, Hale C, Halpern D, Harville E, Hart L, Hswen Y, Kirkpatrick B, McEwen B, Morris G, Orbach R, Palinkas L, Partyka M, Porter D, Prather AA, Rowles T, Scott G, Seeman T, Solo-Gabriele H, Svendsen E, Tincher T, Trtanj J, Walker AH, Yehuda R, Yip F, Yoskowitz D, Singer B
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Framework for a Community Health Observing System for the Gulf of Mexico Region: Preparing for Future Disasters

FRONTIERS IN PUBLIC HEALTH 2020 OCT 15; 8(?):? Article 578463
The Gulf of Mexico (GoM) region is prone to disasters, including recurrent oil spills, hurricanes, floods, industrial accidents, harmful algal blooms, and the current COVID-19 pandemic. The GoM and other regions of the U.S. lack sufficient baseline health information to identify, attribute, mitigate, and facilitate prevention of major health effects of disasters. Developing capacity to assess adverse human health consequences of future disasters requires establishment of a comprehensive, sustained community health observing system, similar to the extensive and well-established environmental observing systems. We propose a system that combines six levels of health data domains, beginning with three existing, national surveys and studies plus three new nested, longitudinal cohort studies. The latter are the unique and most important parts of the system and are focused on the coastal regions of the five GoM States. A statistically representative sample of participants is proposed for the new cohort studies, stratified to ensure proportional inclusion of urban and rural populations and with additional recruitment as necessary to enroll participants from particularly vulnerable or under-represented groups. Secondary data sources such as syndromic surveillance systems, electronic health records, national community surveys, environmental exposure databases, social media, and remote sensing will inform and augment the collection of primary data. Primary data sources will include participant-provided information via questionnaires, clinical measures of mental and physical health, acquisition of biological specimens, and wearable health monitoring devices. A suite of biomarkers may be derived from biological specimens for use in health assessments, including calculation of allostatic load, a measure of cumulative stress. The framework also addresses data management and sharing, participant retention, and system governance. The observing system is designed to continue indefinitely to ensure that essential pre-, during-, and post-disaster health data are collected and maintained. It could also provide a model/vehicle for effective health observation related to infectious disease pandemics such as COVID-19. To our knowledge, there is no comprehensive, disaster-focused health observing system such as the one proposed here currently in existence or planned elsewhere. Significant strengths of the GoM Community Health Observing System (CHOS) are its longitudinal cohorts and ability to adapt rapidly as needs arise and new technologies develop.
Connaughton DM, Dai RF, Owen DJ, Marquez J, Mann N, Graham-Paquin AL, Nakayama M, Coyaud E, Laurent EM, St-Germain JR, Blok LS, Vino A, Klambt V, Deutsch K, Wu CHW, Kolvenbach CM, Kause F, Ottlewski I, Schneider R, Kitzler TM, Majmundar AJ, Buerger F, Onuchic-Whitford AC, Mao YY, Kolb A, Salmanullah D, Chen E, van der Ven AT, Rao J, Ityel H, Seltzsam S, Rieke JM, Chen J, Vivante A, Hwang DY, Kohl S, Dworschak GC, Hermle T, Alders M, Bartolomaeus T, Bauer SB, Baum MA, Brilstra EH, Challman TD, Zyskind J, Costin CE, Dipple KM, Duijkers FA, Ferguson M, Fitzpatrick DR, Fick R, Glass IA, Hulick PJ, Kline AD, Krey I, Kumar S, Lu WN, Marco EJ, Wentzensen IM, Mefford HC, Platzer K, Povolotskaya IS, Savatt JM, Shcherbakova NV, Senguttuvan P, Squire AE, Stein DR, Thiffault I, Voinova VY, Somers MJG, Ferguson MA, Traum AZ, Daouk GH, Daga A, Rodig NM, Terhal PA, van Binsbergen E, Eid LA, Tasic V, Rasouly HM, Lim TY, Ahram DF, Gharavi AG, Reutter HM, Rehm HL, MacArthur DG, Lek M, Laricchia KM, Lifton RP, Xu H, Mane SM, Sanna-Cherchi S, Sharrocks AD, Raught B, Fisher SE, Bouchard M, Khokha MK, Shril S, Hildebrandt F
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Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations

AMERICAN JOURNAL OF HUMAN GENETICS 2020 OCT 1; 107(4):727-742
Congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most frequent birth defects and represent the most common cause of chronic kidney disease in the first three decades of life. Despite the discovery of dozens of monogenic causes of CAKUT, most pathogenic pathways remain elusive. We performed whole-exome sequencing (WES) in 551 individuals with CAKUT and identified a heterozygous de novo stop-gain variant in ZMYM2 in two different families with CAKUT. Through collaboration, we identified in total 14 different heterozygous loss-of-function mutations in ZMYM2 in 15 unrelated families. Most mutations occurred de novo, indicating possible interference with reproductive function. Human disease features are replicated in X. tropicalis larvae with morpholino knockdowns, in which expression of truncated ZMYM2 proteins, based on individual mutations, failed to rescue renal and craniofacial defects. Moreover, heterozygous Zmym2-deficient mice recapitulated features of CAKUT with high penetrance. The ZMYM2 protein is a component of a transcriptional corepressor complex recently linked to the silencing of developmentally regulated endogenous retrovirus elements. Using protein-protein interaction assays, we show that ZMYM2 interacts with additional epigenetic silencing complexes, as well as confirming that it binds to FOXP1, a transcription factor that has also been linked to CAKUT. In summary, our findings establish that loss-of-function mutations of ZMYM2, and potentially that of other proteins in its interactome, as causes of human CAKUT, offering new routes for studying the pathogenesis of the disorder.
Aires-de-Sousa M, Fournier C, Lopes E, de Lencastre H, Nordmann P, Poirel L
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High Colonization Rate and Heterogeneity of ESBL- and Carbapenemase-Producing Enterobacteriaceae Isolated from Gull Feces in Lisbon, Portugal

MICROORGANISMS 2020 OCT; 8(10):? Article 1487
In order to evaluate whether seagulls living on the Lisbon coastline, Portugal, might be colonized and consequently represent potential spreaders of multidrug-resistant bacteria, a total of 88 gull fecal samples were screened for detection of extended-spectrum beta-lactamase (ESBL)- or carbapenemase-producing Enterobacteriaceae for methicillin-resistant Staphylococcus aureus (MRSA) and for vancomycin-resistant Enterococci (VRE). A large proportion of samples yielded carbapenemase- or ESBL-producing Enterobacteriaceae (16% and 55%, respectively), while only two MRSA and two VRE were detected. Mating-out assays followed by PCR and whole-plasmid sequencing allowed to identify carbapenemase and ESBL encoding genes. Among 24 carbapenemase-producing isolates, there were mainly Klebsiella pneumoniae (50%) and Escherichia coli (33%). OXA-181 was the most common carbapenemase identified (54%), followed by OXA-48 (25%) and KPC-2 (17%). Ten different ESBLs were found among 62 ESBL-producing isolates, mainly being CTX-M-type enzymes (87%). Co-occurrence in single samples of multiple ESBL- and carbapenemase producers belonging to different bacterial species was observed in some cases. Seagulls constitute an important source for spreading multidrug-resistant bacteria in the environment and their gut microbiota a formidable microenvironment for transfer of resistance genes within bacterial species.
Hur JY, Frost GR, Wu XZ, Crump C, Pan SJ, Wong ET, Barros M, Li T, Nie PJ, Zhai YJ, Wang JC, Julia TCW, Guo L, McKenzie A, Ming C, Zhou XX, Wang MH, Sagi Y, Renton AE, Esposito BT, Kim Y, Sadleir KR, Trinh I, Rissman RA, Vassar R, Zhang B, Johnson DS, Masliah E, Greengard P, Goate A, Li YM
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The innate immunity protein IFITM3 modulates gamma-secretase in Alzheimer's disease

NATURE 2020 OCT 2; 586(7831):735-740
The IFITM3 innate immunity protein directly binds presenilin near the active site and upregulates gamma-secretase activity and the production of amyloid-beta, and IFITM3 is upregulated in patients with late-onset Alzheimer's disease. Innate immunity is associated with Alzheimer's disease(1), but the influence of immune activation on the production of amyloid-beta is unknown(2,3). Here we identify interferon-induced transmembrane protein 3 (IFITM3) as a gamma-secretase modulatory protein, and establish a mechanism by which inflammation affects the generation of amyloid-beta. Inflammatory cytokines induce the expression of IFITM3 in neurons and astrocytes, which binds to gamma-secretase and upregulates its activity, thereby increasing the production of amyloid-beta. The expression of IFITM3 is increased with ageing and in mouse models that express familial Alzheimer's disease genes. Furthermore, knockout of IFITM3 reduces gamma-secretase activity and the formation of amyloid plaques in a transgenic mouse model (5xFAD) of early amyloid deposition. IFITM3 protein is upregulated in tissue samples from a subset of patients with late-onset Alzheimer's disease that exhibit higher gamma-secretase activity. The amount of IFITM3 in the gamma-secretase complex has a strong and positive correlation with gamma-secretase activity in samples from patients with late-onset Alzheimer's disease. These findings reveal a mechanism in which gamma-secretase is modulated by neuroinflammation via IFITM3 and the risk of Alzheimer's disease is thereby increased.
Gaebler C, Nussenzweig MC
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All eyes on the hurdle race for a SARS-CoV-2 vaccine

NATURE 2020 OCT 22; 586(7830):?
Leading COVID-19 vaccine candidates have progressed through laboratory tests at record speed. Two early clinical trials suggest that immunization delivers a favourable immune response and safety profile, but questions remain.
Kauppi PE, Ciais P, Hogberg P, Nordin A, Lappi J, Lundmark T, Wernick IK
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Carbon benefits from Forest Transitions promoting biomass expansions and thickening

GLOBAL CHANGE BIOLOGY 2020 OCT; 26(10):5365-5370
The growth of the global terrestrial sink of carbon dioxide has puzzled scientists for decades. We propose that the role of land management practices-from intensive forestry to allowing passive afforestation of abandoned lands-have played a major role in the growth of the terrestrial carbon sink in the decades since the mid twentieth century. The Forest Transition, a historic transition from shrinking to expanding forests, and from sparser to denser forests, has seen an increase of biomass and carbon across large regions of the globe. We propose that the contribution of Forest Transitions to the terrestrial carbon sink has been underestimated. Because forest growth is slow and incremental, changes in the carbon density in forest biomass and soils often elude detection. Measurement technologies that rely on changes in two-dimensional ground cover can miss changes in forest density. In contrast, changes from abrupt and total losses of biomass in land clearing, forest fires and clear cuts are easy to measure. Land management improves over time providing important present contributions and future potential to climate change mitigation. Appreciating the contributions of Forest Transitions to the sequestering of atmospheric carbon will enable its potential to aid in climate change mitigation.
Bavley CC, Fetcho RN, Burgdorf CE, Walsh AP, Fischer DK, Hall BS, Sayles NM, Contoreggi NH, Hackett JE, Antigua SA, Babij R, Garc?a NDV, Kash TL, Milner TA, Liston C, Rajadhyaksha AM
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A dual-virus strategy for the deletion of cacan1c within the prelimbic to nucleus accumbens core projection

MOLECULAR PSYCHIATRY 2020 OCT; 25(10):2201-2202
Bellat V, Alcaina Y, Tung CH, Ting R, Michel AO, Souweidane M, Law B
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A combined approach of convection-enhanced delivery of peptide nanofiber reservoir to prolong local DM1 retention for diffuse intrinsic pontine glioma treatment

NEURO-ONCOLOGY 2020 OCT; 22(10):1495-1504
Background. Diffuse intrinsic pontine glioma (DIPG) is a highly lethal malignancy that occurs predominantly in children. DIPG is inoperable and post-diagnosis survival is less than 1 year, as conventional chemotherapy is ineffective. The intact blood-brain barrier (BBB) blocks drugs from entering the brain. Convection-enhanced delivery (CED) is a direct infusion technique delivering drugs to the brain, but it suffers from rapid drug clearance. Our goal is to overcome the delivery barrier via CED and maintain a therapeutic concentration at the glioma site with a payload-adjustable peptide nanofiber precursor (NFP) that displays a prolonged retention property as a drug carrier. Methods. The post-CED retention of Zr-89-NFP was determined in real time using PET/CT imaging. Emtansine (DM1), a microtubule inhibitor, was conjugated to NIP The cytotoxicity of the resulting DM1-NFP was tested against patient-derived DIPG cell lines.The therapeutic efficacy was evaluated in animals bearing orthotopic DIPG, according to glioma growth (measured using bioluminescence imaging) and the long-term survival. Results. DM1-NFP demonstrated potency against multiple glioma cell lines. The half-maximal inhibitory concentration values were in the nanomolar range. NFP remained at the infusion site (pons) for weeks, with a clearance half-life of 60 days. DM1-NFP inhibited glioma progression in animals, and offered a survival benefit (median survival of 62 days) compared with the untreated controls (28 days) and DM1-treated animal group (26 days). Conclusions. CED, in combination with DM1-NFP, complementarily functions to bypass the BBB, prolong drug retention at the fusion site, and maintain an effective therapeutic effect against DIPG to improve treatment outcome.